The American Cancer Society estimates over 226,160 new cases of lung cancer and approximately 160,340 lung cancer deaths in 2012, making it the most common cause of malignancy-related mortality in the United States.1 Non-small cell lung cancer (NSCLC) carries a dismal prognosis with a five-year survival rates estimated to be less than 16%. Poor survival is due, in part, to the fact that 85% of lung cancer cases are diagnosed after metastatic disease progression, when curative treatment options are no longer available. Diagnosis of NSCLC before the development of extensive locoregional or distant metastases promises to improve five-year survival rates to 60% to 80%.2 Efforts have been made since the early 1970s to identify screening methods for early detection of NSCLC. Unfortunately, neither chest radiography nor sputum cytology was proven effective.3-8 Single-arm prospective uncontrolled studies on low-dose computed tomography (LDCT) of the chest screening yielded conflicting results.1, 7 Recently, the National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality with LDCT screening of “high-risk” subjects compared to annual chest X-ray (CXR) with a median follow-up of 6.5 years.8 High-risk was defined by this study to be individuals age 55-74 year old and having greater than 30 pack-year smoking history and having quit less than 15 years prior to randomization.
The approach to indeterminate LDCT screen-detected lung nodules in high-risk populations can represent significant challenges for the clinician. Data from the NLST showed that 24.2% of screening LDCT scans were positive, with 96.4% of these nodules determined to be false positives.8 An individual has an incidence of 33% of a false-positive LDCT scan after two rounds of annual screening and 7% of these individuals will have unnecessary invasive procedures to prove benign disease.9 Avoidance of these unnecessary invasive procedures would benefit subject safety. The analysis for the cost-effectiveness of LDCT screening has not been reported by the NLST at this time; however, estimates from other groups have concluded the added cost of LDCT screening for lung cancer to approximate $1.3 billion to $2.0 billion, annually.9 In addition, it is estimated to cost $240,000 per one life saved by LDCT screening.9 Decreasing the cost of LDCT screening by decreasing the need for subsequent invasive thoracic procedures or continued radiographic follow-up is paramount.
The potential of individual serum biomarkers to predict malignancy in indeterminate lung nodules has been researched and met with limited success. Published data on individual serum biomarkers, most notably cytokeratin 19 fragment (CYFRA) 21.1, carcinoembryonic antigen (CEA), and tissue plasminogen activator in non-small cell lung cancer (NSCLC) show limited sensitivity and specificity, particularly in early-stage disease.10, 11 What is needed to improve the efficacy and cost-effectiveness of the LDCT screening paradigm is a biomarker panel for assigning clinical significance to indeterminate lung nodules that may be used as a companion test to help assign clinical significance to LDCT-detected indeterminate lung nodules or provide a risk of malignancy. What is also needed is a biomarker panel assigning risk for the presence of lung cancer as a primary screen, possibly to indicate who should have further diagnostics (like LDCT imaging or biopsy) performed.